associated with xanthelasma (yellowish patches underneath the skin around the eyelids) corneal arcus (white/grey discoloration of the peripheral cornea) and ...
cholesterol
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Lipid, lipoprotein and cholesterol management in clinical practice Ruth Agar, Lipid Nurse Manager, and Prof Vincent Maher, Consultant Cardiologist, reveal that significant lipid disorders exist in Ireland
L
ipid is a collective term that refers to blood and cellular cholesterol, fats (Triglycerides) and phospholipids. Cholesterol is a fat-like substance that is found in all body cells. It is essential for cell membranes, some hormones, vitamin D and bile acids synthesis. The body is capable of synthesizing sufficient cholesterol for its needs but also acquires cholesterol from dietary sources. To ensure its solubility, cholesterol travels through the bloodstream bound to proteins called apoproteins (eg, apo B) and the complexes are known as lipoproteins. These particles are arranged so that the hydrophobic fatty acids, eg, those in triglycerides, remain on the inside and the hydrophilic free cholesterol, phospholipid head groups and apoproteins lie on their surface. The main lipoproteins are chylomicrons, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low-density lipoproteins (LDL) which are apo B containing and high-density lipoproteins (HDL) which contain apo A-1. The pathways associated with the various lipoproteins are outlined in Figure 1. Essentially, dietary acquired cholesterol and triglyceride are used to form chylomicrons which deliver them to the liver. These in addition to those synthesised in the liver combine with apoproteins to form VLDL particles. They are broken down in the blood stream into VLDL remnants and IDL to form LDL particles. Cholesterol is returned to the liver by HDL particles from peripheral cells and is finally excreted in the bile. The main lipoproteins associated with atherosclerosis
are apo B containing VLDL remnants, IDL, and LDL whereas apo A-1 containing HDL Is considered protective in most instances. Having healthy levels of these lipoproteins is important. A high level of LDL "Lousy, Lethal" cholesterol leads to plaque formation in the arteries. Conversely HDL “Healthy Hoover” cholesterol, transports cholesterol from around the body to the liver for removal.
Figure 1
Figure 2
What is high blood cholesterol? High blood cholesterol is a condition where excess cholesterol containing particles circulate in the blood stream. There are usually no signs or symptoms and therefore people are unaware that they have high cholesterol unless they have some obstructive cardiovascular disease. In those with high cholesterol or insufficient HDL cholesterol, they have an increased cardiovascular risk, especially when associated with diabetes, obesity, high blood pressure and smoking. Coronary heart disease is caused by plaque build-up resulting in atherosclerosis. Plaque consists of cholesterol, fat, calcium, and fibrous tissue. Over time, plaques grow and narrow the coronary arteries which may limit the supply of oxygen-rich blood to the heart. If a plaque ruptures, blood clot formation occurs and if large enough may reduce blood flow (angina) or completely block a coronary artery resulting in a myocardial infarction (MI). Plaque can also build up in other arteries in the body, such as those supplying the brain or limbs, resulting in problems such as transient
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ischaemic attacks, stroke or intermittent claudication. It is now accepted that raised LDL cholesterol levels are causal for atherosclerotic vascular disease. What causes high cholesterol? There is a normally a wellbalanced circulation of lipoprotein particles that help supply the building blocks and energy necessary for normal body function. Due to gene defects related to the enzymes, carrier proteins and receptors involved in lipoprotein transport, alterations in lipoprotein metabolism may occur. This can be particularly problematic when excess lipid is available due to over nutrition, excess body weight or hormonal imbalances. Genetic factors Numerous genes relating to enzymes, structural proteins and receptors influence lipoprotein levels in the body. See figure 2. Disorders range from common, less common and relatively rare. The more prevalent disorders include polygenic hypercholesterolaemia and familial combined hyperlipidaemia. Polygenic high cholesterol occurs where small effects from many different genes result in increasing cholesterol levels over time. Familial combined hyperlipidaemia (FCH) is due to variations in genes controlling lipoprotein synthesis or catabolism via the action of lipoprotein lipase. The latter may present with either elevated cholesterol, triglyceride or both in at least two family members, with a pattern that varies with time and is associated with premature cardiovascular disease. This disorder has a prevalence of 1:100 in the UK. In familial hypercholesterolaemia (FH), patients can present with an LDL receptor mutation, increased production of proprotein sonvertase subtilisin kexin 9 (PCSK9), which reduces LDL receptor numbers, or an apoprotein B100 defect. Ultimately all three cause inadequate clearance of LDL, resulting in higher LDL plasma levels. FH is estimated to occur in 1:200 to 1:500 of the population and is associated with a high cardiovascular risk. This is partly due to the life-long exposure of high cholesterol levels associated with these genetic disorders. If high cholesterol levels remain untreated, long-term exposure accentuates the risk of premature MI and stroke. If the frequency of this condition in Ireland was 1:200, roughly 24,000 Irish people would suffer from FH of which approximately 90 per cent are undiagnosed. One of the main mechanisms by which HDL is antiatherogenic is through reverse cholesterol transport. An apoprotein A1 deficiency, the main apoprotein in HDL, may result in decreased HDL levels possibly increasing cardiovascular risk. Less common conditions include type 3 hyperlipidaemia due to the E2 E2 polymorphism in the Apo E gene that produces equimolar elevations in triglyceride and cholesterol in the presence of diabetes or insulin resistance. This occurs in 1:5,000 and is associated with premature vascular disease. There are rare disorders of chylomicron metabolism and HDL metabolism. According to Heart UK, those affected by lysosomal acid lipase deficiency (LALD)-a cholesterol storage disorder, are estimated at 25 per million. Hypertriglyceridaemia Hypertriglyceridaemia (HTG) is a feature of numerous metabolic disorders including dyslipidaemias, metabolic syndrome and type 2 diabetes mellitus and can increase
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the risk of premature coronary artery disease. According to the literature, severe hypertriglyceridaemia is the most common cause of acute pancreatitis after gallstones and BMDPIPM1BUJFOUTXJUIUSJHMZDFSJEFMFWFMT NNPMMBSFBUSJTL of developing pancreatitis and warrant urgent review and assessment. Modifiable environmental factors Improving ones diet through modification of cholesterol, fat and alcohol intake, together with exercise and smoking cessation are important aspects to favourably modify lipid levels as indicated below. Assessment and management of lipid disorders Assessment A careful and detailed clinical assessment is essential in order to assess individual risk of cardiovascular disease or in cases of severe hypertriglyceridaemia, a pancreatitis risk. History While excess blood lipid levels do not cause any symptoms on their own accord, association with cardiovascular disease and pancreatitis may produce symptoms. It is therefore important to elicit if the patient is complaining of symptoms that may suggest obstructive vascular disease such as: t Angina, shortness of breath or change in exercise tolerance may indicate possible CVD. t Visual changes may indicate evidence/risk of TIA. t Erectile dysfunction in males may serve as a marker for peripheral vascular disease. The risk becomes more pronounced with increasing age, indicating the need for monitoring. t Abdominal pain, radiating to the back, nausea or vomiting may indicate a risk of pancreatitis. Additional important information: Smoking status, alcohol intake and presence of diabetes should also be ascertained because of the associated greater risk from lipid disorders in
Figure 3
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these conditions. A history of premature heart disease in first degree relatives, ie, males < 55 years or females < 60 years is also important as it highlights potential greater risk even when lipid levels are modestly raised. Examination t General appearance, gender, race, body habitus, anthropometric measurements. t Some types of hypercholesterolemia lead to specific physical findings. For example, familial hypercholesterolemia may be associated with xanthelasma (yellowish patches underneath the skin around the eyelids) corneal arcus (white/grey discoloration of the peripheral cornea) and xanthomata (yellowish cholesterol-rich deposits) of the tendons surrounding the fingers, knees and elbows. t Blood pressure and signs of smoking (yellow staining of fingers) should be assessed. t Physical signs of vascular disease such as carotid bruits and the presence or absence of pulses (dorsalis pedis/posterior tibial) should be determined. Ankle Brachial Index (ABI) may be utilised to diagnose peripheral vascular disease. The index is the ratio of the systolic blood pressures in the legs compared to the arms. A low ratio indicates obstructive peripheral artery disease. Laboratory measurements A full lipid profile (FLP) should be ascertained at the first visit preferably prior to treatment initiation. This can be completed within clinic or medical practices using the Cholestech LDX, a finger prick testing kit, which can process results within minutes. The Cholestech LDX by Abbot has been validated at Tallaght Hospital as an accurate tool in point of care testing. Lipid profiles: To fast or not to fast The only reportable difference in the fasting and nonfasting population relates to triglyceride (TG) levels. A Danish population study (consisting of 92,000 participants) highlighted that the normal range of TG in the non-fasting population is 0.3mmol/l higher than in the fasting patient. There were no significant differences between fasting and non-fasting TC, HDL, LDL. Since we are generally in a post prandial state most of the day, non-fasting lipid levels may better reflect our average lipid levels. Further laboratory measurements should include liver and renal profiles, homocysteine, high sensitivity CRP, Hba1c to
Table 1
cholesterol
assess for diabetes, TFT to assess for hypothyroidism and creatinine kinase to assess for muscle damage in those with a history of muscular aches. Pancreatic amylase measurements should be considered for those with pancreatitis risk secondary to severe hypertriglyceridemia. Designated lipid centres such as the ALMAR (Advanced Lipid Management And Research) centre at Tallaght Hospital have access to further risk marker measurements such as Apo A1, Apo B100, lipid electrophoresis, lipoprotein (a), Lp(a) and lipoprint. Lp(a) has been considered a cardiovascular risk factor for many years. It is a risk marker for CVD particularly when associated with elevated LDL levels. Ideally, Lp(a) measurements should be obtained to assess the overall cardiovascular risk. Genetic testing may be considered in those with conditions such as familial hypercholesterolaemia to assess if there is a life-long burden from high cholesterol levels. In the future more genetic testing may guide on likelihood of treatment responses and sub categories of patients at greater risk. Identify associated risk factors Although dyslipidaemia is considered the most important risk factor for cardiovascular disease, its risk is significantly modified by associated risk factors including diabetes, smoking, hypertension, family history of high cholesterol and a strong family history of premature CHD in males < 55 and females < 60 years. Exclude secondary causes of dyslipidaemia When assessing risk and assigning lipid targets for individuals with dyslipidaemia, secondary causes of dyslipidaemia should also be investigated. Acquired hyperlipidaemias often mimic primary forms of hyperlipidaemia and can have similar consequences. Diabetes mellitus, hypothyroidism, nephrotic syndrome, chronic renal failure, high alcohol consumption, medications such as thiazide diuretics, beta blockers, estrogens, some rare endocrine disorders and metabolic disorders may significantly affect lipid levels. It is important to exclude secondary causes and treat these conditions to allow the underlying lipid disorder be detected. Assessing risk Risk charts such as SCORE Systematic Coronary Risk Evaluation (Figure 4) are intended to facilitate risk estimation in apparently healthy persons with no signs of clinical or preclinical disease. SCORE assesses CVD risk using five variables: Gender, smoking status, age, systolic blood pressure and total cholesterol. There are different charts for low risk and high risk countries. Ireland is designated as a low risk country. Based on these scores, individuals are categorised as having low, medium, high and very high risk. Those who have diabetes, renal disease or proven vascular
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disease are already considered as having a very high risk. Based on an individual’s cardiovascular risk, targets for LDL cholesterol are recommended as indicated below. Lipid targets High risk:
